The mechanism proposed previously for the interaction between beta-lactams and exocellular DD-carboxypeptidases-transpeptidases applies to the membrane-bound enzyme system involved in peptide crosslinking during the synthesis of the bacterial wall peptidoglycan. On the basis of this model, the relative effectiveness of beta-lactams as inhibitors of a membrane-bound DD-carboxypeptidase in S. faecalis and of a membrane-bound transpeptidase in Streptomyces R61, respectively, has been shown to be related to the relative effectiveness of the same antibiotics as antimicrobial agents on the relevant bacteria. Therefore: 1) each of these enzymes will be isolated and fully characterized; 2) the other penicillin binding sites which are also present in the plasma membranes of these bacteria will be determined; 3) the exact location of the lysozyme-releasable DD-carboxypeptidase which occurs in the cell envelope of Streptomyces sp and its possible physiological role will be determined; 4) the study will be extended to the Gram-negative, rod-shaped Proteus mirabilis and Proteus vulgaris; 5) because of the high interest of the exocellular R61 enzyme as a model for the mode of action of the beta-lactams, the importance played by the structural features of both the enzyme and the beta-lactams in the reaction will be investigated. BIBLIOGRAPHIC REFERENCES: J.M. Frere, J.M. Ghuysen, A.R. Zeiger and H.R. Perkins. The direction of peptide trimer synthesis from the donor-acceptor substrate N alpha-(acetyl)-N epsilon-(glycl)-L-lysyl-D-alanyl-D-alanine by the exocellular DD-carboxypeptidase-transpeptidase of Streptomyces R61. FEBS Letters, 1976, 63, 112-116. J.M. Frere, J.M. Ghuysen, H. Vanderhaeghe, P. Adriaens and J. Degelaen. Fate of thiazolidine ring during fragmentation of pencillin by exocellular DD-carboxypeptidase-transpeptidase of Streptomyces R61. Nature, 1976, 260, 451-454.